Renal Injury and Salt-Sensitive Hypertension After Exposure to Catecholamines

Abstract

Abstract-We investigated whether chronic infusion of phenylephrine could induce structural and functional changes in the kidney of rats with the subsequent development of salt-sensitive hypertension. Rats were infused with phenylephrine (0.15 mmol/kg per day) by minipump, resulting in a moderate increase in systolic blood pressure (BP) (17 to 25 mm Hg) and a marked increase in BP variability as measured by an internal telemetry device. After 8 weeks, the phenylephrine infusion was stopped with the return of BP to normal, and a nephrectomy was performed for histological studies. Glomeruli were largely spared, but focal tubulointerstitial fibrosis was present, with the de novo expression of osteopontin by injured tubules, macrophage and "myofibroblast" accumulation, and focal increases in mRNA for transforming growth factor ␤ by in situ hybridization. Peritubular capillaries at sites of injury had distorted morphology with shrinkage, rounding, and focal rarefaction, and endothelial cell proliferation was also identified. Rats were randomized to a high (8% NaCl or 1.36 mol/kg) or low (0.1% NaCl or 17 mmol/kg) salt diet. After 4 to 8 weeks, phenylephrine-treated rats on a high salt diet developed marked hypertension, which was in contrast with phenylephrine-treated rats placed on a low salt diet or vehicle-treated rats given a high salt diet. Hypertension after phenylephrine exposure correlated with the initial mean systolic BP (r 2 ϭ0.99) and the degree of BP lability (r 2 ϭ0.99) during the phenylephrine infusion, the amount of osteopontin expressed in the initial biopsy/nephrectomy (r 2 ϭ0.74), and the final glomerular filtration rate (r 2 ϭ0.58). These studies provide a mechanism by which a markedly elevated sympathetic nervous system can induce salt-dependent hypertension even when the hyperactive sympathetic state is no longer engaged. (Hypertension. 1999;34:151-159.) Key Words: phenylephrine Ⅲ renal circulation Ⅲ hypertension, episodic Ⅲ sympathetic nervous system T here is ample evidence that a hyperactive sympathetic nervous system (SNS) is present in some forms of human hypertension, especially in early, borderline essential hypertension. 1 In addition to the acute effects of SNS activation to raise blood pressure (BP), adrenergic stimulation may induce target organ damage by both hemodynamic and nonhemodynamic mechanisms. 2 Adrenergic stimulation can be associated with left ventricular hypertrophy as well as hypertrophy and stiffening of large arteries. Adrenergic agents have also been shown to stimulate vascular smooth muscle cell proliferation and hypertrophy both in vivo and in vitro. 3,4 We have been interested in the potential role of the SNS as a mediator of renal injury. It is known that catecholamine infusions can induce acute elevations in glomerular hydrostatic pressure in association with intense renal vasoconstriction and a fall in renal blood flow (RBF). 5,6 Infusions of norepinephrine can also induce microalbuminuria in both normal and diabetic individuals. 7 A combination of intrarenal and i...

The role of renal microvascular disease and interstitial inflammation in salt-sensitive hypertension

“…32 Eventually, peritubular capillaries are permanently damaged and reduced in number, thus causing ischemia, increasing the oxidative stress, and mediating tubulointerstitial inflammation and impairment of pressure diuresis. In support of this hypothesis, a reduction in peritubular capillary density was demonstrated in experimental models of SSHTN [33][34][35] and in humans with essential hypertension. 36 Hypertension and tubulointerstitial inflammation Although not emphasized in the 1958 classical study of Sommers et al, 27 inflammatory infiltration was a constant feature in the renal biopsies of hypertensive patients and, more importantly, the authors did note 'collections of lymphocytes' in the renal interstitium in about 20% of the hypertensive patients that had minimal or no arteriolar changes.…”

Sleep Apnea and Cardiovascular Disease

“…290 -292 OSA and the Origin and Progression of ESRD The most direct mechanism by which long-standing OSA might contribute to the origin of ESRD is by inducing chronic elevations in BP. OSA could further contribute to the progression of ESRD by acutely increasing sympathetic nerve discharge directed at the kidney and other vascular beds, raising BP during episodes of upper airway occlusion, and chronically accelerating the progression of renal damage, 293,294 with sustained elevations in BP during the awake state. 295,296 OSA has also been linked to glomerular hyperfiltration.…”

Blood pressure-renal blood flow relationships in conscious angiotensin II- and phenylephrine-infused rats

“…The present studies were performed to examine the effects of continuous infusion of ANG II on ambient BP and RBF profiles, as well as the variability of BP-RBF relationships in the presence of modest increases in BP. As phenylephrine (PE) administration has also been reported to have similar effects on BP and renal injury in rats (18,43), experiments were also performed in conscious rats continuously administered PE to evaluate the effects of an ANG II-independent pressor agent on such BP and renal hemodynamic profiles. …”